Benzamide derivatives as antagonists of orexin receptors

Abstract

Disclosed are phenyl-alkylene benzamides useful as orexin antagonists

1. A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen; R 2  is (C 1-3 )alkyl; and R 3  is hydrogen or (C 1-3 )alkyl; or R 2  and R 3  together with the carbon to which they are attached form a (C 3-5 ) cycloalkyl group; or 
 R 1  is (C 1-3 )alkyl; R 2  is hydrogen; and R 3  is hydrogen, or (C 1-3 )alkyl; 
 R 4  and R 5  are independently selected from hydrogen, halogen, NC—, optionally substituted (C 1-6 )alkylCO, optionally substituted (C 1-6 )alkyl, optionally substituted (C 1-6 )alkoxy, optionally substituted (C 1-6 )alkylOCO—, and optionally substituted (C 1-6 )alkylNHCO—; provided that R 4  and R 5  are not both hydrogen; 
 R 6  is hydrogen or halogen; 
 Ar represents an optionally substituted aryl or an optionally substituted 5- or 6-membered aromatic heterocyclyl group containing up to 3 heteroatoms selected from N, O and S; or Ar represents an optionally substituted bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; 
 wherein said optionally substituted Ar is substituted by 1 to 3 substituents independently selected from the group consisting of: phenyl optionally substituted by halogen; a 5- or 6-membered aromatic heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, optionally substituted by (C 1-4 )alkyl; halogen; hydroxy; oxo; cyano; nitro; (C 1-4 )alkyl; hvdroxy(C 1-4 )alkyl; (C 1-4 )alkoxy; hydroxy(C 1-4 )alkoxy; halo(C 1-4 )alkyl; halo(C 1-4 )alkoxy; aryl(C 1-4 )alkoxy; (C 1-4 )alkylthio; hydroxy(C 1-4 )alkyl; (C 1-4 )alkoxy(C 1-4 )alkyl; (C 3-6 )cycloalkyl(C 1-4 )alkoxy; (C 1-4 )alkanoyl; (C 1-4 )alkoxycarbonyl; (C 1-4 )alkylsulfonyl; (C 1-4 )alkylsulfonyloxy; (C 1-4 )alkylsulfonyl(C 1-4 )alkyl; arylsulfonyl; arylsulfonyloxy; arylsulfonyl(C 1-4 )alkyl; (C 1-4 )alkylsulfonamido; (C 1-4 )alkylamido; (C 1-4 )alkylsulfonamido(C 1-4 )alkyl; (C 1-4 )alkylamido(C 1-4 )alkyl; arylsulfonamido; arylcarboxamido; arylsulfonamido(C 1-4 )alkyl; arylcarboxamido(C 1-4 )alkyl; aroyl; aroyl(C 1-4 )alkyl; aryl(C 1-4 )alkanoyl group; and a group R x R y N—, R x OCO(CH 2 ) r , R x CON(R y )(CH 2 ) r , R x R y NCO(CH 2 ) r , R x R y N(CH 2 ) r O, R x R y NSO 2 (CH 2 ) r  or R x SO 2 NR y (CH 2 ) r  where each of R x  and R y  independently represents a hydrogen atom or a (C 1-4 )alkyl group or where appropriate R x R y  forms part of a (C 3-6 )azacycloalkane or (C 3-6 )(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4; 
 wherein when Ar is phenyl, two substituents on adjacent carbon atoms may, together with the ring to which they are attached, form a bicyclic or tricyclic heterocyclyl or carbocyclyl ring system, which may be optionally substituted by halogen or oxo; 
 X is —CH 2 —, or a bond; Y is —NHCO—, or a bond; or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
       2. A compound according to  claim 1  wherein R 1  is hydrogen and R 2  and R 3  are selected from the combinations: methyl/hydrogen, ethyl/hydrogen and methyl/methyl. 
     
     
       3. A compound according to  claim 1  wherein Ar is phenyl, naphthyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl or naphthyridinyl, any of which may be optionally substituted. 
     
     
       4. A compound according to  claim 1  wherein Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, thiazolyl, triazolyl, or pyrazolyl, any of which may be optionally substituted. 
     
     
       5. A compound selected from:
 (R)-benzo[1,3]dioxole-5-carboxylic acid[2-(3,4-dimethoxy-phenyl)-ethyl]-(2-phenyl-propyl)-amide; 
 (R)-2-cyano-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-N-(2-phenyl-propyl)-benzamide) and a pharmaceutically acceptable salt or solvate of either thereof. 
 
     
     
       6. A pharmaceutical composition comprising a compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
       7. A method of treating diseases or disorders where an antagonist of a human orexin receptor is required, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
       8. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to  claim 1  which process comprises reacting a compound of formula (II) with a compound of formula (III): 
       
         
           
           
               
               
           
         
       
       wherein Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are as hereinbefore defined for compounds of formula (I), and Z is a leaving group or a group converted to a leaving group in-situ followed by, optional, conversion to a pharmaceutically acceptable salt or solvate thereof. 
     
     
       9. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       10. A compound according to  claim 1  having a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       11. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       12. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       13. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       14. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       15. A compound according to  claim 1  having the formulaselected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       16. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       17. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       18. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       19. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       20. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       21. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       22. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       23. A compound according to  claim 1  having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Ar is 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt or solvate of any one thereof. 
     
     
       24. A compound according to  claim 1  selected from the group consisting of: 5-bromo-2,3-dihydrobenzofuran-7-carboxylic acid (3,4-dimethoxy-benzyl)-(2-methyl -2-phenyl-propyl)-amide;
 (R,S)-3-acetylamino-N-(3,4-dimethoxy-benzyl)-N-(2-phenyl-propyl)-benzamide; 
 (R,S)-benzothiazole-6-carboxylic acid (3,4-dimethoxy-benzyl)-(2-phenyl-propyl)-amide; 
 3-acetylamino-N-(3-bromo-4-methoxy-benzyl)-N-(2-methyl-2-phenyl-propyl)-benzamide; 
 (R,S)-benzo[1,2,5]oxadiazole-5-carboxylic acid (3,4-dimethoxy-benzyl)-(2-phenyl-propyl)-amide; 
 (R,S)-benzo[1,2,5]thiadiazole-5-carboxylic acid (3,4-dimethoxy-benzyl)-(2-phenyl-propyl)-amide; 
 (R,S)-benzo[1,3]dioxole-5-carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-(2-phenyl-propyl) amide; 
 (R,S)-3-bromo-N-(3-bromo-4-methoxy-benzyl) -N-(2-phenyl-propyl)-benzamide; 
 (R,S)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid[2-(3,4-dimethoxy-phenyl)-ethyl]-(2-phenyl-propyl) amide; 
 (S)-3-bromo-N-(3,4-dimethoxy-benzyl) -N-1-methyl-2-phenyl-ethyl)-benzamide; 
 (S)-3-bromo-N-[2-(3,4-dimethoxy-phenyl) -ethyl]-N-(1-methyl-2-phenyl-ethyl)-benzamide; 
 (S)-benzo[1,3]dioxol-5-carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-(1-methyl-2-phenyl-ethyl)-amide; 
 (R)-benzo[1,3]dioxole-5-carboxylic acid[2-(3,4-dimethoxy-phenyl)-ethyl]-(2-phenyl-propyl)-amide; 
 (R)-2-cyanoN-[2-(3,4-dimethoxy-phenyl)-ethyl]-N-(2-phenyl-propyl)-benzamide); 
 and a pharmaceutically acceptable salt or solvate of any one thereof. 
 
     
     
       25. A compound according to  claim 1  selected from the group consisting of:
 (R,S)-N-(2-benzoylamino-propyl)-3-bromo-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-benzainide; 
 (R,S)-N-(2-benzoylamino-propyl)-5-bromo-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-2-methoxy-benzamide; 
 (S)-3-bromo-N-(3,4-dimethoxy-benzyl)-N-(2-phenyl-propyl)-benzamide; 
 and a pharmaceutically acceptable salt or solvate of any one thereof.